Platinum drug adduct formation in the nucleosome core alters nucleosome mobility but not positioning.
Nucleosome positioning and reorganization regulate DNA site exposure in chromatin. Platinum anticancer agents form DNA adducts that disrupt nuclear activities, triggering apoptosis. Mechanistic insight would aid in the development of improved therapies to circumvent drug toxicity and resistance. We show that platinum adducts formed by reaction of cisplatin or oxaliplatin with the nucleosome core inhibit histone octamer-DNA sliding but do not cause significant alteration of positioning. Thus, adduct formation reinforces positional preferences intrinsic to the DNA sequence, which indicates that modulation of platinum drug site selectivity by histone octamer association may relate to nucleosome-specific properties of DNA. This sheds light on platinum drug-mediated inhibition of chromatin remodeling in vivo and suggests that adducts can shield their own repair and interfere with genomic activities by directly altering nucleosome dynamics.
Wu
Bin
B
Division of Structural and Computational Biology, School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore.
Davey
Curt A
CA
D008958:Models, Molecular; D008968:Molecular Conformation; D009707:Nucleosomes / Q000737:chemistry*; D010984:Platinum / Q000737:chemistry*
D009707:Nucleosomes; D010984:Platinum